Selective allylic oxidation process

ABSTRACT

MULTI-STEP PROCESSES FOR THE PREPARATION OF TRICYCLIC INTERMEDIATES USEFUL IN THE TOTAL SYNTHESIS OF STEROIDS ARE DESCRIBED A FIRST PROCESS STEP INVOLVES TREATMENT OF A DIHYDROXY, DIVINYL COMPOUND WITH BOTH MANGANESE DIOXIDE AND AN AMINE TO PRODUCE A MANNIC BASE INTERMEDIATE. THE RESULTING MANNICH BASE INTERMEDIATE MAY BE REDUCED CATALYSTICALLY AND THEN COUPLED WITH A CYCLIC DIONE TO YIELD A TRICYCLIC KETO DIENE. THIS COMPOUND USEFUL BE REDUCED TO YIELD A TRICYCLIC HYDROXY COMPOUND USEFUL AS AN INTERMEDIATE IN THE TOTAL SYNTHESIS OF STERODIAL COMPOUNDS HAVING KNOWN VALABLE PHARMACOLOGICAL PROPERTIES. ALTERNATIVELY, IT IS POSSIBLE TO DIRECTLY COUPLE THE MANNICH BASE WITH THE CYCLIC DIKETO COMPOUND FOLLOWED BY REDUCTION AND CATALYTIC HYDROGENATION TO YIELD THE TRICYCLIC HYDROXY COMPOUND.

United States Patent US. or. zen-345.9 2 Claims ABSTRACT OF THEDISCLOSURE Multi-step processes for the preparation of tricyclicintermediates useful in the total synthesis of steroids are described. Afirst process step involves treatment of a dihydroxy, divinyl compoundwith both manganese dioxide and an amine to produce a Mannich baseintermediate. The resulting Mannich base intermediate may be reducedcatalytically and then coupled with a cyclic dione to yield a tricyclicketo diene. This compound can be reduced to yield a tricyclic hydroxycompound useful as an intermediate in the total synthesis of steroidalcompounds having known valuable pharmacological properties.Alternatively, it is possible to directly couple the Mannich base withthe cyclic diketo compound followed by reduction and catalytichydrogenation to yield the tricyclic hydroxy compound.

RELATED APPLICATIONS This application is a divisional application ofSer. No. 818,142, filed Apr. 21, 1969, now U.S. Pat. No. 3,631,039,patented Dec. 28, 1971.

BRIEF SUMMARY OF THE INVENTION The present invention relates toprocesses for the preparation of compounds of the following formula:

U is a single or double bond; R is lower alkyl and n is 1 or 2.

-In one preferred aspect of the present invention, compounds of FormulaI where A is and U is a double bond, e.g., compounds corresponding tothe following formula:

where R and n are as above Patented Feb. 13, 1973 are prepared byreacting a Mannich base compound of the formula:

v- OH III where R taken independently is hydrogen or lower alkyl; Rtaken independently is lower alkyl or aralkyl and R and R taken togetherwith the adjacent nitrogen atom form a 5 or 6 membered saturatedheterocyclic ring including at the most one further hetero atom selectedfrom the group consisting of nitrogen and oxygen with a cyclic dione ofthe formula:

where R and n are as above.

Examples of suitable cyclic diones of Formula IV include, for example,Z-methyl-l,3-cyclopenta-nedione (R=methyl, n=l), 2-ethyl 1,3cyclopentanedione (R=ethyl, n=1), 2-propyl 1,3 cyclopentanedione(R=pr0pyl, nl=l), 2-butyl 1,3 cyclopentanedione (R=butyl, 111:1),2-methyl 1,3 cyclohexanedione (R=methyl, 111:2), etc.

The reaction between compounds of Formulas III and IV above isconveniently conducted in an inert organic solvent in the presence of anorganic acid, e.g., acetic acid, and at a temperature in the range offrom about 50 C. to the reflux temperature of the reaction medium, mostpreferably to C. Suitable inert organic so1- vents include, for example,aromatic hydrocarbons such as benzene, toluene and xylene; chlorinatedaromatic hydrocarbons such as chlorobenzene or dichlorobenzene;nitrobenzene; tertiary alcohols such as t-butanol, etc. A most preferredsolvent for this reaction is xylene.

Compounds of Formula III are readily prepared from compounds of theformula:

where R and R are as above in the presence of manganese dioxide tounexpectedly yield an addition product wherein only one of thechemically equivalent vinyl groups has been substituted even in thepresence of more than one mole of amine.

The Mannich base products correspond to compounds of the followingformula:

where R and R are as above and the optical enantiomers thereof.

It should be noted that compounds of Formulas III and VII exist insolution in two tautomeric forms as indicated by sub-Formulas -III(a),III(b), VII(a) and VII(b), respectively. The cyclic structures ofFormulas III(a) and VH(a) are believed to be the lower energy form andthus is favored in the tautomeric equilibrium under most conditions.However, evidence for the existence oftautomeric Formulas III(b) andVII(b) are observed in the infrared wherein carbonyl stretchingabsorption peaks are in evidence. It is to be understood, however, thatthe absolute structure of the compounds of Formulas III and VII is notcritical to the concept of the present invention.

The amines of Formula VI useful in the initial process step of thisinvention may be primary or secondary amines. Suitable primary aminesinclude, for example, the lower alkyl amines such as methylamine,ethylamine, propylamine, n-butylamine, hexylamine, etc., preferablyn-butylamine; aralkylamines such as ot-methylbenzylarnine or amines ofcomplex molecules such as, for example, dehydroabietylamine. Thesecondary amines most preferably include dilower alkylamines which maycontain additional substitutents on the alkyl groups, e.g., phenyl, orcyclic amines. Examples of dilower alkylamines include dimethylamine,diethylamine, methylethylamine, desoxyephedrine, with diethylamine beingof greatest preference. Examples of cyclic amines include pyrrolidineand piperidine while morpholine is an example of a cyclic amine havingan additional heterocyclic atom.

The process for the preparation of compounds of Formula VII is generallyconducted at a temperature in the range of from about to 75 0., mostpreferably in the range from about 25 to 45 C., it being understood thatthe reaction is slightly exothermic and the reaction temperature may besomewhat higher than the original mixing temperature. The reaction maybe conducted in the presence of an added inert organic solvent such as,for example, an aliphatic hydrocarbon such as hexane; a chlorinatedhydrocarbon such as, for example, dichloromethane or chlorobenzenes,e.g., chlorobenzene or dichlorobenzene; or an aromatic hydrocarbon suchas benzene, toluene or xylene. The manganese dioxide used in thisprocess is preferably an active grade which material is obtainable as anarticle of commerce.

The compounds of Formula VII may be catalytically hydrogenated, e.g., inthe presence of metal catalysts such as palladium which may be supportedon a conventional carrier, e.g., charcoal, calcium carbonate, bariumsulfate, etc., to yield the compofunds of Formula III above. Thishydrogenation can be conducted in an inert organic solvent such as, forexample, an aliphatic hydrocarbon such as hexane, aromatic hydrocarbonssuch as, for example, benzene, toluene or xylene, ethers such astetrahydrofuran, or lower alkanols such as ethanol. Conventionalhydrogenation conditions may be employed which include a pressure in therange of from about 0.5 to 50 atmospheres, most preferably in the rangeof from about 1 to atmospheres, and a. temperature in the range of fromabout 0 to O/VZI Q) where R and n are as above VIII and the opticalenantiomers thereof. The selective catalytic hydrogenation is conductedusing a supported palladium catalyst such as palladium on bariumsulfate, calcium carbonate, charcoal, etc. It is also possible toutilize Raney nickel as catalyst in this reaction. Solvents useful withthe palladium catalysts include inert organic solvents such as aliphatichydrocarbons, e.g., hexane; or aromatic hydrocarbons, e.g., benzene,toluene or xylene; ethers such as tetrahydrofuran or lower alkanols suchas ethanol or propanol. Lower alkanols are the solvents of preferencewith Raney nickel catalysts. The reaction may be conducted at a pressurein the range of from about 0.5 to 50 atmospheres, preferably 1 to 10atmospheres, and a temperature in the range of about 0 to 0., preferably20 to 35 C. The hydrogenation of the vinyl group will occur rapidly-withthe quick uptake of 1 mol equivalent of hydrogen. Hydrogenation of theremaining diene system will occur only very slowly under theseconditions and the reaction can be conveniently stopped afterhydrogenation of the vinyl group to yield the desired compounds ofFormula H.

Compounds of Formula VIII above are readily obtained by the reaction ofcompounds of Formula IV with compounds of Formula'VII above. Thisreaction can be conveniently conducted in an acid medium, e.g., aceticacid, and in the presence of an inert organic solvent, most prefera blyan aromatic hydrocarbon such as toluene, benzene or xylene. A mostpreferred solvent of this reaction is xylene. Conditions for thisreaction include a temperature in the range from 60 C. to the refluxtemperature of the reaction medium, with the reflux temperature beingpreferred.

Compounds of Formula I wherein A is OH H and U is a single bond may beprepared in a two-step procedure from compounds of Formula VIII above.The first step of this process involves reduction of the keto group to ahydroxy group utilizing a chemical reducing agent. Suitable chemicalreducing agents for this p'urpose include metal hydrides, e.g., lithiumaluminum hydride, diisobutyl aluminum hydride or sodium borohydride. The

reaction can be conveniently conducted in an inert organic solvent suchas an ether, e.g., tetrahydrofuran and at a temperature in the range offrom about 70 to 60 0., most preferably in the range of from about 10 to20 C. The reaction product corresponds to compounds of the followingformula:

where R and n are as above and the optical enantiomers thereof.

Compounds of Formula IX may then be catalytically hydrogenated to yieldthe desired compounds of Formula I wherein A is where R and n are asabove.

The catalytic hydrogenation of compounds of Formula IX is conducted inthe presence of a catalyst metal, e.g., palladium, which may besupported on a conventional carrier, e.g., charcoal. The hydrogenationis preferably conducted in the presence of an inert organic solvent suchas, for example, an aromatic hydrocarbon such as benzene, xylene ortoluene, an ether such as tetrahydrofuran or a lower alkanol, e.g.,ethanol or propanol. The reaction is conducted at a temperature in therange of from about 0 to 60 0., most preferably in the range from about20 to 35 C. and a pressure in the range of from 0.5 to 50 atmospheres,most preferably in the range of from 1 to atmospheres. Normal conditionsare of highest preference.

In another process aspect of this invention compounds of Formula IX maybe catalytically hydrogenated under the selective conditions employedfor the transformation of compounds of Formula VIII to compounds ofFormula II described above to yield compounds of Formula I wherein A isOHH and U is a double bond, that is compounds corresponding to theformula OH H R where R and n are as above.

Compounds of Formula XI may also be obtained by reduction of compoundsof Formula II using metal hydrides as per the description of thetransformation of Formula VIII to Formula IX compounds previouslydescribed. Compounds of Formula XI may be catalytically hydrogenated togive compounds of Formula X by employing conditions previously describedfor the transformation of compounds of Formula IX to compounds ofFormula X.

It is to be understood that the processes of the present invention areequally useful whether employing racemic mixtures or optical enantiomersof the respective compounds used in each process. For example, ifcompounds of Formula VII are resolved, such as by forming salts ofoptically active acids, e.g., camphorsulfonic acid or tartaric acid orwhere R or R is optically active by direct crystallization of the amineor acid addition salts thereof, e.g., the oxalic acid salt, and the (R)isomer is utilized in the preparation of compound VIII, it is found thatthe carbon bearing substituent R has the absolute configurationcorresponding to the natural steroids.

It is evident to one skilled in the art that if optically activecompounds of Formula VII are employed then the succeeding intermediatesprepared therefrom by use of the processes of this invention will alsobe obtained as optical enantiomers.

The foregoing reaction sequences may be more clearly illustrated byreference to the following reaction scheme;

II IX [H] l A! lHz OH OH R E R H zw H2) EL 1n)n so I XI W X Intermediatecompounds corresponding to Formulas VII, VIII and IX are novel compoundsand are considered within the scope of the present invention. Theproducts of the processes of the present invention, i.e.,

compounds of the Formulas H, X and XI which taken together representgeneric Formula I, are intermediates known in the art to be useful inthe preparation of steroids having valuable pharmaceutical properties.Thus, for example, the utilization of compounds of Formulas II, X and XIfor this purpose is described in Belgian Pat. No. 698,390, publishedNov. 13, 1967.

As used herein the term lower alkyl is meant to include both straightand branched chain hydrocarbon groups of from 1 to 6 carbon atoms suchas, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,secondary butyl, tertiary butyl, pentyl, hexyl and the like. When theterm lower alkyl is used with reference to substituent R, it is meant toinclude straight chain hydrocarbon groups only.

The following examples further illustrate the present invention.

EXAMPLE 1 Preparation of 2-(2-diethylaminoethyl)-2-hydroxy-6-vinyltetrahydropyran A total of 156.2 g. of 3,7-dihydroxy-1,8-nonadieneand 100 g. of diethylamine were dissolved in 2.5 l. of hexane and thesolution was treated with activated manganese dioxide which was added tothe solution portionwise. Addition of manganese dioxide was continueduntil thin layer chromatography indicated the reaction was complete.About 1000 g. of manganese dioxide was utilized. The temperature of thereaction medium rose spontaneously from about 25 C. to about 45 C.during the course of the reaction. Filtration and thorough washing ofthe solid with 3.0 l. of hexane resulted in the recovery of 95 percentof the manganese dioxide. The solvent was removed in vacuo from thefiltrate and a residue comprising crude 2 (2' diethylaminoethyl)-2-hydroxy-6-vinyltetrahydropyran (209 g., 92 percent) was obtained. Thismaterial was of sufficient purity to be utilized in further reactionsteps.

Purification of the product can be achieved by taking up the crude inhexane, extracting with dilute aqueous acid, separating and collectingthe acid phase, neutralizing and back extracting with hexane.

The 3,7-dihydroxy-1,8-nonadiene may be prepared as follows:

Water was distilled under reduced pressure (60-100 mm. Hg) fromcommercial grade aqueous glutaraldehyde (4 kg. of 50 percentconcentration) at 60-90 C. The resulting glutaraldehyde was thendistilled at 20-22 mm. Hg and added immediately at 20 C. to a solutionof vinyl magnesium chloride obtained from magnesium (1.2 kg.) and vinylchloride (4.2 kg.) in 18 l. of tetrahydrofuran containing iodine andethyl bromide in small proportions as catalysts. The reaction mixturewas then treated with ammonium chloride and hydrochloric acid and theproduct extracted from the aqueous phase with tetrahydrofuran ormethylene chloride. The residue remaining after removal of the solventwas distilled to obtain 3,7-dihydroxy-1,8-nonadiene in a yield of 2.162kg. (75.3 percent) with a boiling point of 100-103 C./1

mm. Hg.

EXAMPLE 2 7 Preparation of 2-(2'-diethylaminoethyl)-2-hydroxy-6-ethyltetrahydropyran Crude2-(2'-diethylaminoethyl)-2-hydroxy-6-vinyltetrahydropyran (209 g.)prepared as in Example 1 above was dissolved in 1,500 ml. of hexane andafter the addition of 1 g. of 10 percent of palladium on charcoal wasstirred in a hydrogen atmosphere at 2535 C. until hydrogen uptake at 0.5to 2 atm. ceased (approximately 77-90 percent of theory). Filtration ofthe mixture removed the catalyst and the filtrate was concentrated invacuo to leave a residue containing crude2-(2'-diethylaminoethyl)-2-hydroxyfi-ethyltetrahydropyran which could beutilized without further purification in further steps.

EXAMPLE 3 Preparaton ofdl-3-vinyl-1,2,3,5,6,6a-hexahydro-6amethylcyclopenta [f 11]benzopyran-7(8H)-one A solution containing 227 g. of2-(2-diethylaminoethyl)Z-hydroxy-6-vinyltetrahydropyran in 3.8 1. ofxylene was treated with 112 g. of Z-methyl-1,3-cycl0pentanedione and 1l. of acetic acid. The reaction mixture was heated at reflux for 15minutes. The acid was removed by extraction with water and dilute sodiumbicarbonate solution. The organic phase was collected and the solventsremoved in vacuo. Distillation of the residue at 121-124" C./ 0.6 mm. Hgand recrystallization of the distallate from hexane yielded theabove-titled product as yellow needles (135 g., 58.7 percent). Furtherrecrystallization from hexane yielded product having a melting point of91.8-93.2 C.

EXAMPLE 4 Preparation ofdl-3-ethyl-2,3,5,6,6a,8-hexahydro-6amethylcyclopenta [f] [1]benzopyran-7 8H) -one (a) A mixture containing 6.47 g. of2-methyl-1,3-cyclo pentanedione, 130 ml. of xylene and 65 ml. of glacialacetic acid was heated at reflux for 5 minutes. To the resultingsolution was added during 15 minutes, 13.25 g. of2-(2'-diethylaminoethyl)-2-hydroxy 6 ethyltetrahydropyran in 65 ml. ofxylene under reflux and a nitrogen atmosphere. The reaction mixture isheated at reflux for an additional 15 minutes. The resulting solution iscooled to 25 C. with an ice bath, then washed with 2X ml. of water, 2100 ml. of saturated sodium bicarbonate and then with 1x 100 ml. ofWater. The aqueous solutions are extracted with 2X 200 ml. of benzeneand the combined benzene and xylene solutions are concentrated in vacuoat 55 C. to yield brownish crystals as a residue. The residue istriturated with 50 ml. of hexane, the mixture filtered after 5 minutesand the solid washed with 2X 15 ml. of hexane to yield theabove-captioned product as beige crystals melting at 101-1025 C.

(b) A solution of 460 mg. of dl-3-vinyl-l,2,3,5,6,6ahexahydro 6a methylcyclopenta[f][1]benzopyran- 7 (8H)-one in 10 ml. of toluene wasselectively hydrogenated under normal conditions using 25 mg. of a 10percent palladium on calcium'carbonate catalyst. After 3 hours theuptake of hydrogen was 50 ml. The hydrogenation was then stopped, thecatalyst was filtered off, washed with 2x 10 ml. of toluene and thesolvent evaporated oil from the combined toluene solution to give 425mg. of dl-3-ethyl-2,3,5,6,6a,8-hexahydro-a-rnethyl-cyclopenta [f][1]benzopyran-7(8H)-one as beige crystals, M.P. 101-104 C.

EXAMPLE 5 Preparation of 2-[2'-(1-pyrrolidyl)ethy1]-hydroxy-6-vinyltetrahydropyran Pyrrolidine (1.5 g.) and3,7-dihydroxy-1,8-nonadiene (2.2 g.) in 40 ml. of xylene was treatedwith activated manganese dioxide (20 g.) as in Example 1. After 12hours, the solution was filtered, the recovered manganese dioxide washedwith 6X 50 ml. of dichloromethane and the combined solvents wereevaporated to leave an almost theoretical yield of crude2-[2'-(1-pyrr0lidyl)-ethyl]-2- hydroxy-G-vinyltetrahydropyran which wassuitable for use without further purification.

EXAMPLE 6 Preparation of 2-[2'-(1-piperidy1)ethyl]-2-hydroxy-6-vinyltetrahydropyran The procedure of Example 4 wasrepeated utilizing1.5 g. of piperidine as the amine component. The product obtained inalmost theoretical yield was crude 2-[2'-(1- piperidyl)ethyl]-2-hydroxy-fi-vinyltetrahydropyran which was suitable for use withoutfurther purification.

9 EXAMPLE 7 Preparation of 2-[2-(1-morpholino)ethyl]-2-hydroxy-6-vinyltetrahydropyran The procedure of Example 4 was repeated utilizing1.5 g. of morpholine as the amine component. The product obtained inalmost theoretical yield was crude 2-[2'-(1- morpholino)ethyl]-2-hydroxy6 vinyltetrahydropyran which was suitable for use without furtherpurification.

EXAMPLE 8 Preparation of 2-(Z-n-butylaminoethyl)-2-hydroxy-6-vinyltetrahydropyran A solution containing 3.12 g. of1,8-nonadiene-3,7-diol in benzene containing 3.0 g. of n-butyl-amine wastreated with 40 g. of activated manganese dioxide and the mixture wasstirred at 25-30 C. for 18 hours. The mixture was filtered and themanganese dioxide was washed thoroughly with benzene. The combinedbenzene filtrates were evaporated at 40 C. at 20 mm. Hg and then finallyat 1 mm. Hg to yield crude product as a dark oil.

For purification the oil was taken up in ethyl acetate and with coolingwas treated with 1.2 N hydrochloric acid. Extraction with 3 portions ofethyl acetate removed impurities. The aqueous phase was made basic (withcooling) using 10 N sodium hydroxide. Extraction with four portions ofbenzene, washing of the combined benzene extracts with saturated sodiumchloride solution, drying over anhydrous sodium sulfate, filtration andevaporation as above yielded 4.80 g. of the above-titled product as anoil which was found to be uniform by thin layer chromatography.

EXAMPLE 9 The procedure of Example 3 was repeated utilizing the Mannichbase products of Examples 5, 6, 7 and 8 and 2-methyl-1,3-cyclopentanedione to yield in all cases the desireddl-3-vinyl-1,2,3,5,6,6a-hexahydro-6a-methyl cyclopenta [f][l]benzopyran-7(8H)-one.

EXAMPLE 10 Preparation of 2-(2'-()-a-phenylethylaminoethyl)-2-hydroxy-fi-vinyltetrahydropyran (racemic) A solution of 10.9 g. of3,7-dihydroxy-1,8-nonadiene and 8.48 g. of ()-a-phenylethylamine in 500ml. of benzene was treated under vigorous stirring at 25 C. with 80 g.of activated manganese dioxide. After stirring for 60 hours, themanganese dioxide was filtered off and washed with 2X 100 ml. ofbenzene. After evaporation of the solvent, crude product was obtainedwhich was purified by chromatography on 380 g. of alumina. Fractions(380 ml. each) were taken as follows: 13=pentane; 46=hexane;79=hexane/ether (9:1); 10-12=hexane/ ether (4:1); 1315=hexane/ether(1:1) and 16-18=ether. Fractions 912 were shown to be pure above-titledproduct, combined yield 3.14 g. after removal of solvent.

EXAMPLE 11 Resolution of 2-(2'-()-a-phenylethylaminoethyl)-2-hydroxy-6-vinyltetrahydropyran as the oxalate salt To a solution of 826mg. of purified 2-(2'-(')uphenylethylaminoethyl)-2-hydroxy 6vinyltetrahydropyran in 16 ml. of dioxane there was added a solution of273 mg. of 99.0 percent anhydrous oxalic acid powder. After standing at25 C. for one week the precipitated white crystals were filtered off andwashed with dioxane (2.x 3 ml). There was obtained 243 mg. of theoxalate of the negative rotating enantiomer of2-(2'-(-)-uphenylethylaminoethyl)-2-hydroxy 6 vinyltetrahydropyran; M.P.l19124 C., [a] =24.'5 (c.=l.0, methanol).

Use of acetone instead of dioxane yielded 389 mg. of the oxalate, M.P.11 9-124 C., [a] =24.2 (c.=1.0, methanol).

10 EXAMPLE 12 Preparation of()-3-vinyl-1,2,3,5,6,'6a-hexahydro-6amethyl-cyclopenta[f] [1]benzopyran-7(8H)-one A mixture of 207 mg. ofZ-methyl-1,3-cyclopentanedione, 9.0 ml. of xylene and 2.3 ml. of glacialacetic acid were refluxed under nitrogen for 2 minutes. Then 592 mg. ofthe resolved oxalate salt prepared by the method of Example 11 was addedand the mixture refluxed for /2 hour. The solution was then washed with2X 5 ml. water, 2x 5 ml. saturated sodium bicarbonate solution and 1X 5ml. water. The combined aqueous phases were ex tracted with 2x 20 ml. ofbenzene. The combined xylene and benzene solutions were evaporated andthe residue (330 mg.) was purified by passing it through a columncontaining 16.5 g. of alumina. Fractions of 16.5 ml. each were taken asfollows: 1-10=hexane, 11-13=hexane/ ether (19:1) and 1416=hexane/ether(9:1). layer chromatography analysis showed fractions 7-11 (42.8 mg.after evaporation) to be pure ()-3-vinyl-1,2,3,5, 6,6a-hexahydro 6amethyl-cyclopenta[f] [l]benzopyran- '7(8H)-one, [a] =85.O (c.=l.0,chloroform).

EXAMPLE 13 Preparation of(-)-3-ethyl-1,2,3,5,6,6a-hexahydro-6amethyl-cyclopenta[f][l]benzopyran-7(8H)-one A total of 132 mg. of(-)-3-vinyl-1,2,3,5,6,6a-hexahydro 6a methyl-cyclopenta[f][l]benzopyran-7(8H)- one in 4.0 ml. of toluene was selectivelyhydrogenated under normal conditions using 25 mg. of a 10 percentpalladium on barium sulfate catalyst. The hydrogenation was stoppedafter an uptake of 16 ml. of hydrogen. After the catalyst was filteredoff and the solvent evaporated, mg. of crude product was obtained as aresidue which was then purified by chromatography on 5.5 g. of alumina.A series of 5.5 ml. fractions were taken as follows: 110=hexane andl1-13=hexane/ether (19:1). Thin layer chromatography analysis showedfractions 3-10 (75.2 mg. after evaporation of solvent) to be (-)-3-ethyl1,2,3,5,6,6a hexahydro 6a methyl-cyclopenta[f] [l]benzopyran 7(8H) one,[ot] =-118.8 (c. =1.0, chloroform). Recrystallization from pentane/hexane (1:1) yielded 35.5 mg. of crystalline product, M.P. 98-101 C.,[a] 123.8 (c.==1.0, chloroform).

EXAMPLE 14 Preparation ofdl-3-vinyl-1,2,3,5,6,6a,7,8-octahydro-6amethy1-cyclopenta[f 1[l]benzopyran-7-ol A total of 20 g. ofdl-3-vinyl-1,2,3,5,6,6a-hexahydro- 6a methy1-cycylopenta[f][l]benzopyran-78H) -one dissolved in 200 ml. of tetrahydrofuran wasadded to a suspension of lithium aluminum hydride (2 g.) intetrahydrofuran (200 ml.) at 0 C. After one hour a total of 24 ml. ofwater was added and the solution filtered. Evaporation of the solventand recrystallization of the residue from hexane yielded theabove-titled product melting at 110-112 C.

EXAMPLE 15 Preparation of dl-1,2,3,5,6,6a,7,8,9,9a-decahydro-3-ethyl-6a-methyl-cyclopenta[f] [l]benzopyran-7-ol (a) Crude dl-3-vinyl1,2,3,5,6,6a,7,8 octahydro-6amethyl-cyclopenta[f] [l]benzopyran-7-ol(41.4 g.) in 400 ml. of toluene was hydrogenated at normal conditions inthe presence of 4 g. of 10 percent of palladium on charcoal catalyst.After absorption of hydrogen ceased (slightly less than theoreticalamount taken up) the solution was filtered free from the catalystand'the product was recovered by evaporation of the solvent to yield 41g. of cruded1-1,2,3,5,6,6a-,7,8,9',9a-decahydro-3-ethyl-6amethyl-cyclopenta[f]'[l]benzopyran-7-olas an oil which is suitable for use in further transformations withoutpurification.

(b) A mixture containing 3-ethyl-1,2,3,5,6,6a,7,8-octa- 1 1hydro-6a-methyl-cyclopenta[f] [l]benzopyran-7-ol 160 ml. of methanol,1.6 ml. of 3 N sodium hydroxide and 0.8 g. of 5 percent palladium oncharcoal is stirred at room temperature under a hydrogen atmosphere. Theuptake of hydrogen stopped after 2 hours during which time 520 ml. ofhydrogen was taken up. After addition of 0.3 ml. of acetic acid, thecatalyst is filtered off and the filtrate evaporated to dryness to yield4.9 g. of dl-1,2,3,5,6,6a,7, 8,9,9a-decahydro 3 ethyl 6amethyl-cyclopenta[f] [1] benzopyran-7-ol.

EXAMPLE 16 Preparation of 2-[methyl-(l-methyl-Z-phenylethyl)aminoethyl]-2-hydroxy-6-vinyltetrahydropyran A mixture of3,7-dihydroxy-l,8-nonadiene (15.6 g., 0.1 m.),dl-phenyl-Z-methylaminopropane (14.9 g., 0.1 m.) and active manganesedioxide (120 g.) was suspended in toluene (200 ml.) with stirring andthe temperature rose from 22 C. to 41 C. After 3 days nodihydroxynonadiene could be detected by thin layer chromatography. Thereaction mixture was filtered and the manganese dioxide was washed Withtoluene (300 ml.). The product was extracted from the toluene solutionswith 300 ml. of hydrochloric acid (1 N) and recovered from the acid bythe addition of 15 percent aqueous sodium hydroxide solution (250 ml.)and hexane (100 ml.). Separation of the hexane layer and distillation ofthe hexane left the above-titled product (20.5 g.) as a light brown oil.

EXAMPLE 17 Preparation of3-ethyl-1,2,3,5,6,6a,7,8-octahydro-6amethylcyclopenta[f] [l]benzopyran-7-ol A solution of 1 g. of3-ethyl-1,2,3,5,6,6a,7,8-octahydro- 6a-methyl-cyclopenta[f][l]benzopyran-7(8H)-one in 20 ml. of tetrahydrofuran is added during 15minutes to a stirred mixture of 110 mg. of lithium aluminum hydride in25 ml. of tetrahydrofuran maintained at 0 C. and under an atmosphere ofnitrogen. After an additional hour of stirring at 0 C., the mixture isadded to a concentrated sodium hydroxide solution. The resultingsolution is filtered and evaporated to yield 982 mg. of S-ethyl-1,2,3,5,6,6a,7,8-octahydro 6a methyl-cyclopenta[f] [1] benzopyran-7-ol,M.P. 107109 C.

12' What is claimed is: 1. A process for the preparation of compounds ofthe formula with an amine of the formula where R; and R are as above inthe presence of manganese dioxide. V 2. The process of claim 1 whereinsaid amine is diethylamine.

References Cited UNITED STATES PATENTS 3,655,695 4/1972 Andrews 260340.5

NORMA S. MILESTONE, Primary Examiner US. Cl. X.R.

260-293.67, 247.7 A, 345.2, 326.5 D, 584 A, 635 R

